Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

Aegida Neradova, Grzegorz Wasilewski, Selene Prisco, Peter Leenders, Marjolein Caron, Tim Welting, Bert van Rietbergen, Rafael Kramann, Jürgen Floege, Marc G Vervloet, Leon J Schurgers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

BACKGROUND: Hyperphosphatemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate have been shown also to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K-binding by PBs may offset beneficial effects of phosphate level reduction on reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC.

METHODS: We performed 3/4Nx in rats, after which warfarin was given for three weeks to induce vitamin K-deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for eight weeks. Primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-Computed Tomography (μ-CT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analyzed in vasculature using ucMGP specific antibodies.

RESULTS: Combination of high vitamin K2 diet and PB treatment significantly reduced VC as measured by μ-CT, for both thoracic (p = 0.026) and abdominal aorta (p = 0.023), compared to MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2 treated groups in both thoracic (p<0.01) and abdominal aorta (p<0.01) as compared to high vitamin K2 treated groups. Moreover, high vitamin K diet and PBs led to reduced vascular oxidative stress.

CONCLUSION: In an animal model of kidney failure with vitamin K-deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Original languageEnglish
Pages (from-to)652-662
Number of pages11
JournalNephrology Dialysis Transplantation
Volume37
Issue number4
Early online date30 Oct 2021
DOIs
Publication statusPublished - 25 Mar 2022

Keywords

  • chronic kidney disease
  • matrix Gla protein
  • phosphate binders
  • vascular calcification
  • vitamin K2
  • MATRIX GLA-PROTEIN
  • CORONARY-ARTERY CALCIFICATION
  • SMOOTH-MUSCLE-CELLS
  • LANTHANUM CARBONATE
  • HEMODIALYSIS-PATIENTS
  • AORTIC CALCIFICATION
  • CALCIUM
  • DISEASE
  • RATS
  • PROGRESSION

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